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of beta-glucuronidase-resistant \"glucuronides\" of valproic acid after intrabiliary administration in the rat: intact absorption, fecal excretion and intestinal hydrolysis.\nThe major metabolite of valproic acid (VPA) is its beta-glucuronidase-susceptible glucuronide conjugate (VPA-G). At slightly alkaline pH such as in bile, VPA-G undergoes intramolecular rearrangement into at least six beta-glucuronidase-resistant isomers (VPA-G-R). The in vivo disposition of VPA-G-R was compared with those of VPA-G and VPA, each at 100 mg of VPA per kg, after intrabiliary administration to surgically prepared rats fasted during the experiments. Administered VPA was rapidly and completely absorbed into blood (peak 30 micrograms of VPA per ml at 0-2 hr). Administered VPA-G was predominantly hydrolyzed (beta-glucuronidase) in the intestine and liberated VPA absorbed into blood (peak 5 micrograms of VPA per ml at 6-9 hr). Administered VPA-G-R was disposed along at least three pathways: (1) part excretion, mainly unchanged, in feces (12% of dose); (2) part absorption (intact) from gut to blood and excretion in urine as VPA-G-R (3.6% of dose); and (3) part hydrolysis in the intestine (most likely by nonspecific esterases) with absorption of liberated VPA into blood (peak 2 micrograms of VPA per ml at 12-24 hr). The VPA/VPA-G/VPA-G-R composition of recovered dose in bile and urine was determined after all doses. In fed, nontraumatized rats given VPA-G-R p.o. at 100 mg of VPA per kg, 50% of the dose was recovered (mainly unchanged) in feces, a portion was absorbed intact into blood (2.5% of dose VPA-G-R excreted in urine) and the remainder hydrolyzed in the intestine with absorption of liberated VPA into blood.(ABSTRACT TRUNCATED AT 250 WORDS)"}

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of beta-glucuronidase-resistant \"glucuronides\" of valproic acid after intrabiliary administration in the rat: intact absorption, fecal excretion and intestinal hydrolysis.\nThe major metabolite of valproic acid (VPA) is its beta-glucuronidase-susceptible glucuronide conjugate (VPA-G). At slightly alkaline pH such as in bile, VPA-G undergoes intramolecular rearrangement into at least six beta-glucuronidase-resistant isomers (VPA-G-R). The in vivo disposition of VPA-G-R was compared with those of VPA-G and VPA, each at 100 mg of VPA per kg, after intrabiliary administration to surgically prepared rats fasted during the experiments. Administered VPA was rapidly and completely absorbed into blood (peak 30 micrograms of VPA per ml at 0-2 hr). Administered VPA-G was predominantly hydrolyzed (beta-glucuronidase) in the intestine and liberated VPA absorbed into blood (peak 5 micrograms of VPA per ml at 6-9 hr). Administered VPA-G-R was disposed along at least three pathways: (1) part excretion, mainly unchanged, in feces (12% of dose); (2) part absorption (intact) from gut to blood and excretion in urine as VPA-G-R (3.6% of dose); and (3) part hydrolysis in the intestine (most likely by nonspecific esterases) with absorption of liberated VPA into blood (peak 2 micrograms of VPA per ml at 12-24 hr). The VPA/VPA-G/VPA-G-R composition of recovered dose in bile and urine was determined after all doses. In fed, nontraumatized rats given VPA-G-R p.o. at 100 mg of VPA per kg, 50% of the dose was recovered (mainly unchanged) in feces, a portion was absorbed intact into blood (2.5% of dose VPA-G-R excreted in urine) and the remainder hydrolyzed in the intestine with absorption of liberated VPA into blood.(ABSTRACT TRUNCATED AT 250 WORDS)"}